Lecture 2 to 3: PD Flashcards
Drugs affecting Ligand-gated Ion Channels
- Local anesthetics: all local anesthetics bind to intracell site
- Benzodiazepines: hyperpolarize GABAaR
- Ligand can either be:
- extracell mediator: ACh, GABA, aspartate or glutamate
- intracell: Ca2+, cAMP or cGMP
Drugs affecting G Protein-linked Receptors
- Albuterol, a β2-agonist, is used for asthma.
- Propranolol, a β-antagonist, is used for hypertension.
- Bethanechol, a muscarinic agonist, is used for atonic bladder.
- Ipratropium, a muscarinic antagonist, is used for asthma.
cAMP-Mediated Hormonal Responses
- Breakdown of glycogen in liver: β-adrenoceptors & glucagon receptors
- Breakdown of TAGs in adipose tissue: β-adrenoceptors
- Increased heart rate and contraction force: β-adrenoceptors
- Relaxation of smooth muscle: β-adrenoceptors
Ca2+-mediated responses
- Smooth muscle contraction
- Increased force of contraction of cardiac muscle
- Secretion from exocrine glands
- Neurotransmitter release from neurons
- Hormone release
Ligand-regulated Transmembrane Enzymes
- polypeptides consisting of:
- an extracellular hormone-binding domain and
- cytoplasmic enzyme domain.
- Tyrosine kinase: insulin, EGFR, NGFR, PDGFR
- Ex. Imantinib,
- serine/threonine kinase,
- guanylyl cyclase.
Cytokine Receptors
- Cytokine receptors respond to many peptide ligands, such as growth hormone, prolactin, erythropoietin, and interferons.
- no intrinsic enzymatic activity
- bind an intracellular JAK -> STAT/STAT dimers translocate to the nucleus where they regulate transcription of specific genes.
Statins
- HMG CoA reductase inhibitor -> By inhibiting cholesterol synthesis statins deplete intracellular supply of cholesterol.
- Depletion of intracellular cholesterol leads to up-regulation of LDL receptors in hepatocytes -> increased clearance of LDL from the blood.
Structural Proteins Drug
vinca alkaloids bind to tubulin
Actions of Drugs Not Mediated by Binding to Receptors
- Antacids
- Mesna
- Mannitol
- Cholestyramine
- Dimercaprol
Extracell enzymes
- ACE found in blood
- ACE inhibitors inhibit formation of AT II to Rx sodium & water retention & lower BP
- Ex. Captopril
Mesna
- Mesna mops up acroleine
- Reacts in the bladder with acroleine, a metabolite of the anticancer drug cyclophosphamide, thus preventing hemorrhagic cystitis.
Mannitol
increases the osmolarity of various body fluids. This effect can promote diuresis or reduction of cerebral edema.
Cholestyramine, colestipol and colesevelam
Bind bile acids in the intestinal lumen and prevent their reabsorption. Used to treat hyperlipidemia.
Dimercaprol
chelates heavy metals.
Graded Dose-Response Curves
hyperbolic curve according to the following equation:
Receptor Binding of Drugs
Irreversible Competitive Antagonism drug examples
- Phenoxybenzamine: alpha-adrenoceptor blocker for rx pheochromocytoma
- Aspirin
- Omeprazole: PPI
- Some authors refer to this type of antagonism as noncompetitive.
- Ex. Ketamine: NMDAR
Noncompetitive Antagonism
- aka allosteric antagonism.
- insurmountable.
- Emax is decreased.
Partial agonist
An agonist that has a lower Emax than a full agonist is a partial agonist. (This refers to the question with the graphs showing the dose responses of norepinephrine and Drug X).
Nonreceptor antagonists
- Functional: indirect & physiological
- Chemical
Indirect Antagonism
- antagonist binds to a macromolecule in the pathway that links the receptor to the effect.
- Ex.a drug that inhibits PKA blocks the effects of a β-adrenoceptor agonist.
Physiological Antagonism
One agonist opposes another agonist, but through different receptors.
Ex. Epi & Histamine
Chemical Antagonism
protamine, a protein which is positively charged, counteracts the effects of heparin, an anticoagulant that is negatively charged.
Drug Selectivity
A drug is selective if there is at least a 10-fold difference between its binding affinity for its first target (the target which mediates the therapeutic effects) versus its second target (which mediates adverse effects).
The greater the difference, the more selective the drug is.
Inverse agonist
- reverse the constitutive activity of a receptor.
- famotidine, losartan, metoprolol and risperidone.
Quantal Dose-Effect Curves
- based on a graded response (as seen above) or on an all-or-nothing (quantal) response
- plots fraction of the population
